Project Summary/Abstract The highly innervated periodontal ligament attaches the root of the tooth to alveolar bone and provides tactile sensation to teeth. This sensory feedback, called osseoperception, is critical for controlling tooth contact and manipulating food during mastication. However, the sensory nerves resident in the periodontal ligament are lost when a natural tooth is replaced by a dental implant. As the bone forms a structural and functional connection with the implant, a process known as osseointegration, some sensory nerves have been observed to approach the peri-implant bone. However, it is not known if these sensory nerves contribute to osseointegration or play a role in establishing osseoperception. In this project, our lab will use validated knockout and reporter mice to visualize and disrupt functional signaling of sensory nerves in peri-implant bone in established and novel models of dental implant osseointegration. The long-term goal of our research is to increase the utility and stability of dental implants. In this project, our main objective is to determine the precise timeline and requirement for innervation in peri-implant bone. Our central hypothesis is that sprouting of the craniofacial nerves into the peri- implant bone is critical for the overall stability of the implant and the degree of osseoperception following surgery. We will directly test our hypothesis in two specific aims. In the first aim, we will characterize the expression of NGF as well as TrkA sensory nerve innervation of peri-implant bone during osseointegration of submerged and immediately loaded dental implants using three reporter mouse strains. In the second aim, we will determine the effect of modulating NGF-TrkA signaling on implant osseointegration and osseoperception. NGF-TrkA signaling will be impaired using a chemical-genetic knockout mouse, and stimulated using exogenous NGF. The results of this study will clearly define the requirements of NGF-TrkA signaling for implant osseointegration and provide a pathway for leveraging this signaling axis for improving osseoperception. Importantly, this proposal fits directly into a conceptual framework that will lead to future R01-level funding for this important research area.